Chapter40).Kidneysize, renalplasmaflow,glomerularfiltrationrate,andtransportratesforanumberofsubstancesarealsoincreasedbythyroidhormone.
Non-thyroidal illness syndrome (NTIS), also known as euthyroid sick syndrome, occurs frequently in severely ill patients who require hospitalization. NTIS is characterized by decreased levels of both circulating thyroid hormone and TSH caused by CNS-mediated suppression of the hypothalamic-pituitary-thyroid axis. In addition, peripheral metabolism of T4 to inactive rT3 is also increased. A similar pattern is seen upon prolonged fasting. Although it remains incompletely understood, NTIS has been proposed to represent a physiological energy-sparing adaptation to chronic illness or starvation.
Mechanism of Thyroid Hormone Action
Formanyyearsitwasthoughtthatthyroidhormonesdiffusepassivelyacrosscellmembranes,butthisisnowknowntorequiretransportproteins.TheseincludethemonocarboxylatetransportersMCT8andMCT10,whicharecapableoftransportingbothT4andT3acrosstheplasmamembrane(
Fig.
42.13
Fig.42.5 ).Recently,mutationsinMCT8havebeenshowntocauseanX-linkeddevelopmentalsyndromeinhumanscharacterizedbyelevatedT3levels,musclehypoplasia,andsevereneurologicalimpairment.Anothertransporter,OATP1C1,appearstoplayaroleintransportofT4acrosstheblood-brainbarrier.
ManybutnotallT3actionsaremediatedthroughitsbindingtooneofthemembersofthethyroid hormone receptor (TR) family. TheTRfamilybelongstothenuclearhormonereceptorsuperfamilyoftranscriptionfactors(seealso ).Inhumanstherearetwothyroidhormonereceptorgenes,THRA andTHRB, locatedonchromosomes17and3,respectively,thatencodethenuclearthyroidhormonereceptors.THRAencodesTRα, whichisalternativelysplicedtoformtwomainisoforms.TRα1isabonafideTR,whereastheotherisoformdoesnotbindT3.THRBencodesTRβ1 andTRβ2, whicharehigh-affinityreceptorsforT3.ThetissuedistributionofTRα1andTRβ1iswidespread.TRα1isstronglyexpressedincardiacandskeletalmuscle.TRα1istheprimarymediatorofthyroidhormoneactionontheheart.Incontrast,TRβ1isexpressedmainlyinbrain,liver,andkidney.TRβ2expressionisrestrictedtothepituitaryandcriticalareasofthehypothalamus,aswellasthecochleaandretina.T3actingviaTRβ2isresponsibleforinhibitingexpressionoftheprepro-TRHgeneintheparaventricularneuronsofthehypothalamusandtheβ subunitTSHgeneinpituitarythyrotropes.Thusthenegative-feedbackeffectsofthyroidhormoneonbothTRHandTSHsecretionarelargelymediatedbyTRβ2.
•Fig. 42.13 Mechanismsofthyroidhormoneaction,includingtheroleofMCTtransporters,D2deiodinase,andTR-RXRheterodimers.CoA,coactivator;CoR,co-repressor;RXR,retinoidXreceptor.
Fig.42.13 ).UnligandedTR-RXRbindstothyroidresponseelementsintargetgenesandrecruitsco-repressorsthatinhibitgenetranscription.UponT3binding,theco-repressorsarereleased,andcoactivatorsarerecruitedtothehormone-receptorcomplex,inducinggenetranscription.